INVITED REVIEW Binocular vision in amblyopia: structure, … · 2019-10-12 · INVITED REVIEW...

INVITED REVIEW

Binocular vision in amblyopia: structure, suppressionand plasticityRobert F Hess1, Benjamin Thompson2 and Daniel H Baker3

1Department of Ophthalmology, McGill Vision Research, McGill University, Montreal, Canada, 2Department of Optometry and Vision Science,

University of Auckland, Auckland, New Zealand, and 3Department of Psychology, University of York, York, UK

Citation information: Hess RF, Thompson B & Baker DH. Binocular vision in amblyopia: structure, suppression and plasticity. Ophthalmic Physiol Opt

2014; 34: 146–162. doi: 10.1111/opo.12123

Keywords: amblyopia, binocular vision,

plasticity, suppression, treatment

Correspondence: Robert F Hess

E-mail address: [email protected]

Received: 18 September 2013; Accepted: 17

January 2014

Abstract

The amblyopic visual system was once considered to be structurally monocular.

However, it now evident that the capacity for binocular vision is present in many

observers with amblyopia. This has led to new techniques for quantifying suppres-

sion that have provided insights into the relationship between suppression and

the monocular and binocular visual deficits experienced by amblyopes. Further-

more, new treatments are emerging that directly target suppressive interactions

within the visual cortex and, on the basis of initial data, appear to improve both

binocular and monocular visual function, even in adults with amblyopia. The aim

of this review is to provide an overview of recent studies that have investigated

the structure, measurement and treatment of binocular vision in observers with

strabismic, anisometropic and mixed amblyopia.

General introduction

Amblyopia is a neuro-developmental disorder of the visual

cortex that occurs when binocular visual experience is dis-

rupted during early childhood. The disorder is usually diag-

nosed on the basis of reduced visual acuity in an otherwise

healthy eye.1 However, amblyopia is characterized by a

range of visual deficits that affect both monocular and bin-

ocular visual function.2 For many years these deficits were

interpreted within a framework assuming that amblyopes

are anatomically monocular and lacked any functional bin-

ocularity. Within this view, any residual binocular interac-

tions were purely suppressive and secondary to the loss of

monocular function. However, recent findings have pro-

vided strong evidence for intact binocular processes in

adult amblyopes that may have appeared to have been lost

but were, in reality, suppressed under binocular viewing

conditions.

Furthermore, current evidence indicates that suppression

plays a primary role in both the binocular and monocular

deficits experienced by patients with amblyopia. These

findings have led to new approaches to the treatment of

amblyopia that target suppressive interactions within the

visual cortex. Here we review studies indicating that

binocular function is present in amblyopia and describe the

techniques that have been developed to quantify suppres-

sion in patients with amblyopia. We also present combined

data from studies investigating the use of novel treatments

that target suppressive interactions within the amblyopic

visual cortex.

Inferring the architecture of the amblyopic visualsystem

In this section, we summarise results indicating that the

amblyopic visual system has the capacity for binocular

vision and the architectures of computational models that

are based upon these results.

Binocular summation

A common measure of binocular function is to assess the

improvement on a particular task when the stimuli are pre-

sented to two eyes, rather than one. For detection of low

contrast grating stimuli the binocular improvement is

about a factor of 1.4–1.8 in normal observers.3,4 This ‘bin-

ocular summation’ is beyond that expected for probabilistic

combination of two independent inputs, and so implies the

© 2014 The Authors Ophthalmic & Physiological Optics © 2014 The College of Optometrists

Ophthalmic & Physiological Optics 34 (2014) 146–162

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Ophthalmic & Physiological Optics ISSN 0275-5408

existence of physiological mechanisms that integrate infor-

mation from the two eyes.

In amblyopia, binocular summation is typically reported

as being absent or greatly reduced.5–8 Many researchers

concluded from this that binocular combination simply did

not occur in amblyopes, consistent with early physiological

work on cats with surgically induced strabismus.9 But there

is an alternative explanation. Because contrast sensitivity is

greatly reduced in the amblyopic eye, perhaps it simply

provides too little drive to produce a measurable contribu-

tion in standard summation experiments. If the signal to

the amblyopic eye were boosted, might normal levels of

binocular summation occur?

This possibility was tested by Baker et al.,10 who adjusted

the contrast of the stimulus presented to the amblyopic eye

so that it was as strong (relative to its own detection thresh-

old) as the stimulus presented to the fellow eye. This proce-

dure yielded normal levels of binocular summation,

providing strong evidence that amblyopes retain binocular

mechanisms. This surprising result provided a foundation

for treatments designed to recover the latent binocular

capacity of amblyopes (sect. ‘Suppression’). This in turn

raises the question of whether the lack of binocular func-

tion under normal viewing conditions is merely a conse-

quence of, or if it is additional to, the monocular

amblyopia. The following sections discuss a number of

masking studies that have addressed this question.

Pedestal masking

A longstanding proposal to explain reduced sensitivity in

amblyopia is an active process of suppression from the fel-

low eye. Dichoptic masking has been proposed as an index

of interocular suppression, with the assumption that it

should be more profound in amblyopia. Several studies

have used a dichoptic pedestal masking paradigm, where a

high contrast mask in one eye impedes detection of similar

target patterns shown to the other eye. Early work6 con-

cluded that interocular suppression was normal in amblyo-

pia, because dichoptic masking functions did not differ

substantially between amblyopic and normal observers.

However, these authors tested very few subjects, so their

results may not be generally applicable.

Harrad and Hess11 repeated the experiment on a larger

number of amblyopes with varying aetiologies. Some of

their results resembled those of the previous study,6 but

they also found evidence for stronger masking from the fel-

low to the amblyopic eye, and weaker masking in the oppo-

site direction. These findings support the notion that some

amblyopes exhibit abnormal suppression of the affected

eye. A more recent study12 that examined strabismic

amblyopes found either normal or weaker-than-normal

suppression of the amblyopic eye for this type of task. This

difference could be due to the heterogeneity of amblyopic

symptoms, or might be due to methodological differences

between the studies. In addition, it may be that the pedestal

masking paradigm lacks the power to reveal differences in

interocular suppression (see Figure 7 in ref. 12 for further

details). We will discuss the implications of these findings

in sect. ‘Models of amblyopia’ below.

As a point of reference for dichoptic presentation one

can display the pedestal and target to the same eye, for

example the amblyopic eye. The task then becomes one of

increment detection, and produces a characteristic ‘dipper’

function. Bradley and Ohzawa13 compared dipper func-

tions in the two eyes of a pair of amblyopes, and found an

upward and rightward shift, such that masking was

increased even at high pedestal contrasts (a similar result

has been reported at higher spatial frequencies14). This

intriguing finding (since confirmed12) suggests that internal

noise might be increased in the amblyopic eye (i.e. its

responses are more variable) compared with the fellow eye

(an alternative is that the overall response is reduced, but

this account is less well supported by computational model-

ling12). This is because, unlike increases in suppression that

shift the dipper diagonally (causing the dipper handles to

superimpose, see ref. 15), a vertical shift is produced only

by changing the signal to noise ratio.16 If noise is increased

in the amblyopic eye, this could be assessed directly using

the noise masking paradigm (e.g. ref. 17). The next section

summarises studies that have attempted this.

Noise masking in amblyopia

By adding external noise to a stimulus, an estimate of the

internal noise in the detecting channel can be obtained

when the external noise is of sufficient contrast to raise

detection thresholds.17 Several studies have applied this

paradigm to compare the level of internal noise across am-

blyopic and fellow eyes within individual observers. One

such study18 found clear evidence for increased internal

noise in the amblyopic eyes of two of their four observers,

with the remaining two observers showing a pattern more

consistent with poor information extraction (calculation

efficiency). For letter identification though, little increase

in internal noise was found, but much poorer calculation

efficiency was evident.19

External noise studies using more sophisticated tech-

niques (e.g. classification image and double pass methods)

have also concluded that internal noise is elevated in the

amblyopic eye20–22 though it is unclear whether this is addi-

tive, multiplicative or both.12,21 For example, double pass

consistency is lower in the amblyopic eye, consistent with

increased internal noise.20 Increased noise at the psycho-

physical level might be caused by fewer active neurons

(leading to lower signal to noise ratios) or inappropriate



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RF Hess et al. Binocular vision in amblyopia

connections between neural populations. Evidence favour-

ing the latter possibility was reported,23 though this conclu-

sion was based in part on the lack of a difference in contrast

discrimination performance between amblyopic and fellow

eyes in their observers. As detailed in sect. ‘Pedestal mask-

ing’, other studies have found a substantial difference on

this task,12–14 so both explanations may be correct.

Perceived phase and perceived contrast

A recent body of work has extended a paradigm developed

by Ding and Sperling24 to investigate amblyopia.25–27

Observers are presented with two gratings, shown

separately to each eye with variable phases and contrasts

(Figure 1). They are required to judge the perceived phase

(and sometimes also perceived contrast) of the resulting

binocular percept. Amblyopes show various abnormal

behaviours on this task, consistent with a reduction in the

weight given to the signal in the amblyopic eye, and some-

times with additional suppression from the fellow eye (see

sect. ‘Models of amblyopia’). However, a critical point

demonstrated by this paradigm is that amblyopes do not

respond as though they see only the image shown to the fel-

low eye, or the amblyopic eye, in isolation. This supports

the idea that they are able to integrate information binocu-

larly, despite the signals from the amblyopic eye being

degraded in various ways. So, amblyopes do have a form of

binocular single vision, consistent with the finding of a bin-

ocular advantage at detection threshold.10 This realisation

has prompted the development of several computational

models of amblyopia.

Models of amblyopia

Baker et al.12 took a model developed to explain normal

binocular combination4 and asked how it needed to be

(a)

(b)

(c)

Figure 1. An illustration of the stimuli and paradigms used to measure interocular suppression. (a) The dichoptic global motion coherence paradigm.

(b) The dichoptic global orientation coherence paradigm. (c) The binocular phase combination paradigm. See sect. ‘Methods of measuring suppres-

sion’ to ‘The orientation coherence test’ for further details.



148

Binocular vision in amblyopia RF Hess et al.

changed to account for the pattern of contrast discrimina-

tion functions measured from eight strabismic amblyopes.

They added several ‘lesions’ to the model, including absent

binocular combination, and suppression from the fellow

eye onto the amblyopic eye. Surprisingly, these two modifi-

cations were unable to account for any of the key features

of the data. Instead, a very different picture developed of

the architecture of the amblyopic visual system. In the most

successful model, binocular combination and interocular

suppression are normal. However, the input to the amblyo-

pic eye is attenuated at an early stage, and subject to

increased levels of noise. These two small modifications

correctly predicted all of the main findings from that study.

However the fact that increased suppression was not

required was a consequence of the pedestal masking para-

digm used in this study and does not imply that it is

absent.

Huang et al.26,27 made similar modifications to the bin-

ocular model of Ding and Sperling24 to account for their

phase and contrast matching data in amblyopes. They con-

firmed the importance of monocular attenuation with

intact binocular combination, and also found evidence for

increased interocular suppression. Ding et al.25 made fur-

ther refinements to the gain properties of this class

of model to account for several subtle patterns in their

amblyopic data.

Interim summary

We can extrapolate from these studies some general points

about contrast vision in amblyopia. First, binocular mecha-

nisms do appear to exist in the human amblyope, and

involve both summation and suppression of signals across

the eyes. But the amblyopic signal is weaker, noisier, and

may be strongly suppressed by signals in the fellow eye.

These factors combine so that, for typical high contrast

scenes, most of the information available to the observer

comes from the fellow eye. So, amblyopes can be structur-

ally binocular, yet appear functionally monocular, in that

they base their responses in natural viewing tasks on the

input from the fellow eye.

Suppression

History

As described above, suppression within the context of bin-

ocular vision refers to an inhibitory influence of the fellow

eye over the amblyopic eye when both eyes are viewing. It

has been assumed that the role of suppression is to stop

information from the amblyopic eye reaching perception to

prevent visual confusion or diplopia. However, evidence

for this assumption within clinical research is mixed at best.

Initially in the 1950s and 1960s suppression was a hot topic

and the work of Travers28 in Australia, Pratt-johnson29 in

the UK and Jampolski30 in the USA stand out. They care-

fully plotted suppression scotomata and related their size

and position in different forms of strabismus. There was a

consensus that the scotomata were localized and involved

the region of the visual field in the deviated eye that corre-

sponded to the fovea in the fixing eye, sometimes extending

to include the foveal region of the deviating eye. In the fol-

lowing three decades, interest in suppression waned and

while its presence may have been documented in clinical

examinations, not much use was made of it. More recently,

there has been a revival in research into suppression which

involves new and much less dissociative ways of measuring

it31–33 and treatment interventions which directly target

suppression (described in sect. ‘Suppression as a target for

amblyopia treatment’). In our opinion, suppression is the

enemy in terms of restoring binocular function and its

elimination is a necessary first step in any binocular ther-

apy.34–36 For others who worry about the possibility of pro-

ducing diplopia, suppression is their friend, ensuring that

when both eyes are open there is only vision from one eye.

In a lot of ways we are still in the dark ages when it comes

to suppression, opinions rage for and against its elimina-

tion, but little evidence is furnished to support either camp.

The renaissance in thinking about suppression only came

when we developed a means of numerically quantifying its

strength. Once we had a number, rather than a binary on/

off measure, we could ask questions that are addressed in

detail below such as; how does suppression vary in amblyo-

pia?, how is suppression distributed across the visual field?

Is suppression similar in strabismics and ansiometropes?,

and how can we modulate suppression?

Methods of measuring suppression

Understanding suppression has been impeded by the lack

of quantitative measures as most clinical tests, such as the

Worth 4 Dot test, only indicate whether suppression might

or might not be present. Recently, a number of different

tests have been devised, two based on global processing

(form and motion) and another involving local phase and

contrast (Figure 1).

The motion coherence test

This test involves the dichoptic presentation of noise ele-

ments (having a random motion direction) to one eye and

signal elements (having the same coherent motion direc-

tion) to the other eye37 (Figure 1a). The noise presented to

one eye makes it more difficult to detect the direction of

the signal in the other eye. In binocularly normal individu-

als with no strong dominance, it does not matter which eye

sees the signal and which eye sees the noise; the dichoptic

interactions are balanced.38 However, this is no longer the

case in amblyopes. Owing to suppression, performance is



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better when the noise is presented to the ‘suppressed’

amblyopic eye and worse when signal is in the amblyopic

eye. Suppression can be measured by assessing how much

the contrast of the stimulus presented to the fellow fixing

eye has to be reduced to reach a point where it does not

matter which eye sees the signal and which sees the noise,

task performance is equal. This can only occur when infor-

mation from the two eyes is combined equally (i.e. with the

same weight) and, being a global motion task, this

approach involves an assessment of suppression which

relies on extra-striate function (possibly dorsal). In the ori-

ginal version37 of this technique, blocks of signal to one eye

and noise to the other eye were presented using randomly

interleaved staircases. An abbreviated version involves the

presentation of signal to the amblyopic eye and noise of

variable contrast to the fellow eye.39 More recently, we have

devised a version of the test specifically for high anisome-

tropes in which dot size is randomized to ensure that

aniseikonia does not provide a cue for signal noise segrega-

tion.40

The orientation coherence test

This test is identical in principle to that described above for

motion coherence but uses a task involving orientation

coherence41 that has been adapted42 for dichoptic presenta-

tion (Figure 1b). The motivation was to assess suppression

using a task that relies on the extra-striate cortex (possibly

ventral).

The phase test

In this test, also referred to in sect. ‘Perceived phase and

perceived contrast’, the two eyes view suprathreshold sinu-

soidal gratings of equal but opposite spatial phase (e.g.

�45° and +45°) (Figure 1c). If the fused percept has an

equal contribution from each eye then the perceived phase

will be at the arithmetic sum of each eye’s phase (i.e. 0).

The interocular contrast can be manipulated and the phase

in the fused percept measured to ascertain the degree of

any binocular imbalance (i.e. suppression). Typically a low

spatial frequency of 0.3 c/d is used and the perceived phase

is measured using a thin line aligned to the peak of the

waveform.24,26

Suppression and amblyopia

Until recently it was accepted that suppression was inver-

sely related to the depth of amblyopia43 and it has been

often assumed that the nature of suppression differed fun-

damentally between strabismic and anisometropic amblyo-

pes. Evidence for the inverse relationship between

suppression and the depth of amblyopia came from earlier

laboratory work43 which involved nine patients one third

of whom were alternating strabismics. Alternating

strabismics typically have suppression (which may be very

strong44) but no amblyopia and therefore are distinct from

strabismic amblyopes. The alternators within the sample of

patients examined in the earlier study biased the correlation

in the negative direction. More recently, Li et al.45 under-

took a study of suppression using the motion coherence

test described above on a much larger sample of amblyopes

with constant strabismus, anisometropia or both. Figure 2

shows the strength of suppression quantified as the fellow

eye contrast at which normal binocular combination

occurred (lower contrast = stronger suppression) as a func-

tion of letter acuity difference between the amblyopic and

fellow eyes. There is a comparable degree of suppression in

the anisometropic and strabismic populations (although

individuals differ) and stronger suppression is associated

with a greater acuity deficit (the sloping solid line is the best

linear fit to the data). Other studies have now corroborated

this result.42,46,47

The regional distribution of suppression

Since the work of Travers,28 Jampolski30 and Pratt-

Johnson,29,48 the word scotoma has always been synony-

mous with suppression. This early work using handheld

perimetric techniques argued for the existence of well-local-

ized regions of suppression strategically located in the am-

blyopic visual field as described above. We recently

developed a novel means49 of measuring the regional extent

of suppression within the central 20° of the visual field and

re-investigated this issue. The stimulus is shown in Figure 3

and a summary of the results in Figure 4. The measurement

involves dichoptic contrast matching of different segments

of dichoptically presented annuli. The results shown in

Figure 4 suggest that while suppression extends throughout

Figure 2. Mean fellow eye contrast at balance point (relative to 100%)

as a function of interocular acuity difference (Log MAR) for 43 patients

with amblyopia. Lower values on the Y axis indicate stronger suppres-

sion (see sect. ‘Suppression and amblyopia’ for details). There was a sig-

nificant negative correlation (p < 0.001) indicating that stronger

suppression was associated with greater acuity loss in the amblyopic

eye. Figure reproduced from ref. 45.



150


the central 20°, it is greater in the central region. In the cen-

tral field, the 80% contrast segment is seen to be perceptu-

ally reduced to 10% or less. The overall magnitude and

regional distribution of suppression appears to be similar

in strabismic and anisometropic amblyopia. We found no

evidence of localized islands of suppression, though it must

be pointed out that the spatial resolution of our test may

have missed any very fine structure.

Modulating suppression

Short-term monocular occlusion

Short-term (e.g. 2.5 h) monocular occlusion in observers

with normal vision can alter the balance of binocular

interactions. Once the occluding patch is removed, the con-

tribution from the previously patched eye to the binocular

percept increases. This was first shown using binocular riv-

alry50 whereby the image shown to the previously patched

eye becomes dominant. We investigated this effect further51

using the motion coherence test,37 the phase test26 and the

dichoptic contrast test26 and found good support for this

novel modulation of binocularity in normal observers.

Examples of the results for the phase and motion coherence

tests are shown in Figure 5.

Although the effect is temporary, lasting only 30 min, it

is robust and involves both the primary and extra-striate

visual cortex because motion coherence is more of an

extra-striate function than contrast or phase matching.

(a) (b)

Figure 3. The annular-based suppression mapping stimulus. Panel (a) depicts the 40 regions of the visual field that were tested. The radius of the

most eccentric ring is 10°. Panel (b) depicts the dichoptic testing arrangement One segment was shown to the fellow eye (FFE) and the remaining seg-

ments from the same annulus were shown to the amblyopic eye (AME). The targets shown in (b) are subjectively aligned prior to the test. The observer

varied the luminance of the segment with respect to the mean background luminance (i.e. contrast) shown to the fellow eye to match the perceived

contrast of the segments from the same annulus shown to the amblyopic eye. The remaining annuli were shown to both eyes at 80% contrast. Figure

from ref. 49.

Figure 4. Average suppression maps for observers with normal binocular vision (n = 10) and amblyopes with (n = 10) and without (n = 4) strabis-

mus. Amblyopia is associated with significantly stronger suppression than that found in normals. The colour maps indicate the magnitude and extent

of suppression across the central field, the graphs the average suppression for each population. Figure from ref. 49.



151


Although the mechanism is not well understood, it must

involve binocular processes because if one measures mon-

ocular contrast thresholds after patching, the threshold of

the previously patched eye drops while the threshold of the

unpatched eye increases, reflecting a reciprocal (i.e. binocu-

lar) effect.51

Comparable effects can also be seen in amblyopes,

whereby if the amblyopic eye is patched (the opposite of tra-

ditional patching therapy) then the amblyopic eye’s subse-

quent contribution to the binocular percept is strengthened.

A comparison of the effects of short-term occlusion in nor-

mals and amblyopes on the phase test is shown in Figure 6.

The time course of the strengthening effect shown in Fig-

ure 6 is different in normals and amblyopes. In amblyopes

it appears to be more sustained; compare the effects at the

time point T3, where the effect is seen to be reducing for

normals but increasing for amblyopes. Contrast thresholds

are affected in a reciprocal manner with the previously

patched eye having lower thresholds and the unpatched

eye exhibiting higher thresholds on removal of the patch

(Figure 6c). This approach, the opposite of traditionally

occlusion therapy, may offer hope as a means of improving

binocular function in amblyopes by redressing the imbal-

ance cause by chronic suppression. It also suggests that

patching therapy may increase suppression by inadvertently

strengthening the fellow eye. If this is so we are left with an

interesting conundrum; how do we explain the improve-

ment in acuity coexisting with increasing suppression that

may occur after standard occlusion therapy?

Other means of modulating suppression

Suppression can be modulated in a variety of ways

that involve reducing the drive from the fellow eye. For

example, optical blur, neutral density (ND) filters and Ban-

gerter filters placed over the fellow eye will result in less

suppressive drive and hence a more balanced binocular

outcome. Figure 7 shows how neutral density filters, which

change mean luminance but not contrast, affect binocular

combination in a population of observers with normal bin-

ocular vision.52

Figure 7 shows measurements of binocular balance in

terms of the contrast ratio for the signal and noise within

the dichoptic motion coherence task.37 A contrast ratio of

unity indicates balanced weights for each eye’s input for

binocular vision. Results are shown for different subjects,

the denser the filter in front of one eye, the more the bal-

ance shifts in favour of the unfiltered eye. Lens blur and

Bangerter filters have similar effects.53 Similarly, in amblyo-

pia where there is an initial imbalance of the inputs of the

two eyes due to suppression, lens blur, neutral density fil-

ters or Bangerter filters could potentially be used in front of

the sighted eye to reduce suppression and re-balance the

inputs of the two eyes.53,54 However there is more to con-

sider than just suppression because removal of suppression

is a necessary but not sufficient step for restoring functional

binocular vision (i.e. stereopsis). Both neutral density filters

and Bangerter filters are less than ideal choices when it

comes to stereoscopic function.53 The way in which they

affect the signal emanating from the sighted eye turns out

to be particularly detrimental for stereopsis. While it has

been known for some time (Pulfrich Effect) that neutral

density filters introduce a delay to the visual response, there

is also more recent evident that there is also a temporal fil-

tering. Both effects serve to reduce the temporal correla-

tion55 needed for stereoscopic function. Bangerter filters

are composed of randomly arranged micro-particles which

(a)

(b)

Figure 5. The effect of 2.5 h of monocular occlusion with either a light-tight patch or a diffuser on the binocular phase combination task and the

dichoptic global motion coherence task. (a) Experimental protocol, (b) Patching effects on the binocular phase combination task (left panel) and dich-

optic global motion coherence task (right panel). Error bars represent standard errors. Figure from ref. 51.



152


result in a spatial decorrelation of the images in the two

eyes therefore fundamentally reducing stereo processing.53

Lens blur which simply reduces the contrast in a spatial fre-

quency dependent fashion (i.e. more so at high spatial fre-

quencies) is the best of the three types of partial occlusion

as it still supports stereopsis for low spatial frequencies (i.e.

coarse disparities).53

Interim summary

Suppression can be measured using a variety of tech-

niques that allow for the contribution of each eye to

the binocular percept to be quantified. Using such

techniques it has been shown that stronger suppression

is associated with greater visual dysfunction in amblyopia

and that suppression extends throughout the central 20°of the visual field in both strabismic and anisometropic

amblyopia. Suppression can be modulated in both

observers with normal binocular vision and amblyopes

using ND filters, optical blur and Bangerter filters, how-

ever only optical blur is compatible with stereopsis. In

addition, recent data indicate the occlusion of one eye

results in a subsequent strengthening of that eye’s contri-

bution to binocular combination. This provides a new

possibility for amblyopia treatment which is the topic of

the next section.

(a)

(b)

(c)

Figure 6. (a) The time line of the patching and testing protocol. (b) Measurement of binocular balance using the phase test after patching of the am-

blyopic eye for each of four observers with amblyopia (S1–S4). The red lines with open dots in each panel represent the time course of the perceived

phase change for each amblyopic observer, the blue lines and filled dots represent the average results of five normal controls after patching of one

randomly selected eye. Displacement below the baseline represents a strengthening of the patched eye’s contribution to the binocular percept. Error

bars represent standard errors. (c) contrast threshold changes as a result of the above patching protocol.



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Suppression as a target for amblyopia treatment

Evidence presented in the preceding sections supports the

idea that individuals with amblyopia have the capacity for

binocular vision, but that this capacity is suppressed under

normal viewing conditions. Furthermore, it appears that

suppressive or inhibitory interactions within the visual cor-

tex may play a central role in the loss of both monocular

and binocular vision that characterizes amblyopia. Stronger

suppression is associated with poorer stereopsis and poorer

amblyopic eye visual acuity in humans40,45–47 and compel-

ling links between suppression and visual dysfunction have

been found in animal models of amblyopia and strabis-

mus,56,57 particularly the direction relationship between

these two in V1 and V2.56 Initial evidence also indicates

that stronger suppression is associated with a poorer

response to occlusion therapy in children,47 even when fac-

tors such as pre-treatment visual acuity and stereopsis are

accounted for ref. 46. This raises the possibility that sup-

pression not only masks latent visual capabilities58 but also

gates visual cortex plasticity.59 In this context, interventions

that directly target suppressive interactions within the

visual cortex may be particularly relevant to the treatment

of amblyopia. New treatments for amblyopia are highly

desirable as current treatments, whilst effective at improv-

ing amblyopic eye acuity, are not ideal (see ref. 60 for a

recent discussion of the issues involved).

Non-invasive brain stimulation and amblyopia

Non-invasive brain stimulation techniques can be used to

modulate fundamental properties of neural systems such as

excitation and inhibition.61 These techniques have been

intensively studied in the context of neuro-rehabilitation as

abnormal patterns of inhibition and excitation have been

implicated in a wide range of neurological disorders. For

example, beneficial effects of non-invasive brain stimula-

tion have been reported for disorders such as depression,

stroke, tinnitus, Parkinson’s disease and chronic pain.62–66

The two most prevalent forms of non-invasive brain stimu-

lation are transcranial magnetic stimulation (TMS) and

transcranial direct current stimulation (tDCS). TMS

involves the generation of brief, targeted magnetic fields

which pass harmlessly through the scalp and generate a

weak electrical current in the underlying region of cor-

tex.16,67 When multiple pulses of TMS are administered in

close succession, either as a train of pulses (a technique

known as repetitive TMS or rTMS68) or a series of ‘bursts’

(e.g. theta burst stimulation or TBS69), the stimulation can

transiently alter excitation and inhibition within the stimu-

lated region. tDCS involves the use of a weak (1 or 2 mA)

direct current passed between two large head-mounted

electrodes positioned over the brain regions to be stimu-

lated. Cathodal stimulation tends to decrease excitability of

the stimulated neural population whereas as anodal stimu-

lation often has the opposite effect.70 rTMS, TBS and tDCS

are effective when delivered to the visual cortex modulating

factors such as contrast sensitivity, motion perception,

visual evoked potentials and phosphene thresholds (the

intensity of a single pulse of TMS delivered to the occipital

lobe required to induce the percept of a phosphene; a

measure of visual cortex excitability).71–76

A series of recent studies have investigated the possibility

that non-invasive stimulation of the visual cortex can

improve vision in adults with amblyopia.77–80 The rationale

for applying non-invasive brain stimulation to amblyopia

is manifold. Firstly, rTMS, TBS and tDCS have been shown

to modulate abnormal inter-hemispheric patterns of sup-

pression/inhibition within the human motor cortex sug-

gesting that these techniques can reduce pathological

suppression.63,81 Secondly, the effects of brain stimulation

have been shown to interact with ongoing neural activity

within the stimulated brain region. This allows for distinct

neural populations to be targeted even when the popula-

tions inhabit the same region of stimulated cortex.82 In par-

ticular, brain stimulation may act to restore homeostasis to

neural populations.83 This is relevant to amblyopia as the

resolution of brain stimulation does not allow for separate

ocular dominance columns to be targeted, however the

stimulation may differently affect neural inputs from the

amblyopic and fellow eye by virtue of their differing levels

of excitation and inhibition (as described in the sections

above). Thirdly, brain stimulation techniques may act to

reduce intra-cortical inhibition68 which has been strongly

implicated as a ‘break’ on visual cortex plasticity in animal

models of amblyopia.84 Finally, anodal tDCS in particular

Figure 7. The contrast ratio between the eyes on the dichoptic global

motion coherence task as a function of the strength of neutral density

filter placed over the non-dominant eye for observers with normal bin-

ocular vision. A ratio of 1 on the Y-axis indicates normal binocular com-

bination. Lower ratios indicate that greater contrast has to be presented

to the eye with the ND filter for normal binocular combination to be

achieved. The dashed line is the best linear fit and shows that greater

neutral density (ND) filter strengths require greater contrast imbalances

to achieve normal binocular combination. Each symbol represents a dif-

ferent observer. From ref. 52.



154


has been shown to reduce GABA levels within the human

motor cortex85 and behavioural evidence suggests that a

similar explanation may hold for the human visual cor-

tex.86 This is of interest in the context of amblyopia as

GABA is thought to play a key role in suppression of inputs

from the amblyopic eye within the visual cortex.57 We

therefore hypothesized that non-invasive brain stimulation

may reduce suppression of inputs from the amblyopic eye

within the visual cortex and/or enhance visual cortex

plasticity.

Current evidence is generally consistent with this

hypothesis (Figure 8). Specifically, we have shown that

non-invasive brain stimulation can improve contrast sensi-

tivity in at least a subset of adults with amblyopia. In the

first study to address this question we measured contrast

sensitivity for low and high spatial frequency Gabor targets

(the exact spatial frequency was tailored for each patent)

before and after an inhibitory rTMS protocol (1 Hz stimu-

lation, n = 9 patients) and an excitatory protocol (10 Hz

stimulation, n = 6 patients) delivered to the primary visual

cortex.80 Stimulation of the motor cortex was used as a

control condition. Both types of rTMS resulted in signifi-

cant improvements in contrast sensitivity (a mean

improvement of approximately 40%) when high spatial fre-

quency targets were viewed by the amblyopic eye (seven

out of nine patients improved for 1 Hz and six out of six

for 10 Hz, including the two patients who did not improve

for 1 Hz). No improvements were found for the low spatial

frequency target for which the amblyopic eyes did not show

a pronounced contrast sensitivity deficit at baseline. Fur-

thermore, improvements were not found for the fellow eye

after visual cortex stimulation or for either eye after motor

cortex stimulation, indicating that the rTMS effects specifi-

cally targeted amblyopic eye function. The improvements

were transient however, with thresholds returning to base-

line within approximately 24 h after stimulation. In a fol-

low-up study we investigated the effect of repeated

administration of rTMS (in this case continuous TBS;

cTBS) over five consecutive days in four adults with ambly-

opia.79 The acute effects of a single stimulation session

(measured in five patients) resulted in improvements in

contrast sensitivity for the amblyopic eye of a similar

magnitude to the original study. Furthermore there was a

cumulative effect of cTBS on contrast sensitivity over the

first two sessions which stabilized over subsequent sessions

and endured for up to 78 days.

Improvements in contrast sensitivity have also been

found in a subset of adults with amblyopia after anodal

tDCS of the visual cortex (20 min at 2 mA).78 Of 13

adults tested, eight showed improvements in amblyopic

eye contrast sensitivity after anodal tDCS (an average of

27% improvement) whereas five showed the opposite

effect. No reliable improvements for either group were

found for amblyopic function after cathodal stimulation

(a) (b)

0

0.5

1

1.5

2

2.5

3

0 0.5 1 1.5 2 2.5 3

Con

trast

sen

sitiv

itypo

st (l

og)

Con

trast

sen

sitiv

itypo

st (l

og)

Contrast sensititvity pre (log)

Contrast sensititvity pre (log)

cTBS1Hz rTMS10Hz rTMSAnodal tDCS

0

0.5

1

1.5

2

2.5

3

0 0.5 1 1.5 2 2.5 3

Figure 8. A comparison of log contrast sensitivity for a fixed high spatial frequency before, after (panel a) and 30 min after (panel b) different types

of non-invasive stimulation of the visual cortex (continuous theta burst; cTBS, 1 and 10 Hz repetitive transcranial magnetic stimulation; rTMS, and

anodal transcranial direct current stimulation; tDCS). Data points above the unity lines indicate an improvement. N = 27 adults, and the same partici-

pants are shown in both panels. Participants with 10 Hz rTMS data (n = 6) also took part in the 1 Hz rTMS experiment. On average across all studies

contrast sensitivity improved 0.09 log units directly after stimulation (95% CI 0.005–0.02) and 0.2 log units 30 min after stimulation (95% CI 0.1–

0.3). As described in the main text, changes did not occur for control conditions within these studies which included cathodal tDCS, motor cortex

stimulation, fellow eye measurements and the use of low spatial frequency targets for which there was less of a contrast sensitivity deficit for the

amblyopic eye. Data replotted from ref. 78–80.



155


or for the fellow fixing eye. Previous studies applying

anodal tDCS to other neurological disorders have also

reported groups of responders and non-responders87

suggesting that this type of brain stimulation may only

be of use for a subset of participants. To ensure that

anodal tDCS was having an effect on the visual cortex,

fMRI measurements of visual cortex activation in

response to counter-phasing checkerboard stimuli pre-

sented to either the amblyopic or non-amblyopic eye

were made after real and sham anodal tDCS in a group

of responders (n = 5). After sham tDCS there was a

greater response throughout the primary and extrastriate

visual cortex when observers viewed with their fellow

relative to their amblyopic eye. This reduction in the

ability of the amblyopic eye to drive neural responses

throughout the visual cortex has been reported in a

number of previous fMRI studies (e.g. ref. 88) and may

reflect a chronic suppression of information from the

amblyopic eye. Notably, this response asymmetry

between the two eyes was significantly reduced after real

anodal tDCS suggesting that anodal tDCS acted to

equate or ‘balance’ the neural response to input for the

two eyes possibly by reducing chronic suppression. This

rebalancing was most pronounced within V2 and V3.78

More work with larger numbers of patients and a variety

of visual function measures will be required to assess the

potential for the clinical use of brain stimulation tech-

niques in amblyopia treatment. However the current

data show that visual function can be transiently

improved in some participants, after a brief intervention,

possibly due to a reduction in the strength of suppres-

sive in interactions within the visual cortex.

Binocular treatment of amblyopia

A related approach to the treatment of amblyopia that is in

a more advanced state of development involves dichoptic

perceptual learning.34 The first version of this treatment

was based on the dichoptic global motion task modified for

the measurement of suppression that is described above

(sect. ‘Suppression and amblyopia’). Knowing that binocu-

lar function was possible in adults with amblyopia when

the contrast of the images shown to each eye was offset suf-

ficiently in favour of the amblyopic eye, we wanted to know

whether binocular combination could be strengthened. In

our first experiment, ten adults with strabismic amblyopia

practiced the dichoptic global motion task intensively over

a period of several weeks.34,35 At the end of the study six

out of nine participants no longer needed a contrast differ-

ence between the two eyes to allow for normal binocular

combination of the signal and noise. Furthermore, visual

acuity improved by an average of 0.26 LogMAR (95% CI

0.15–0.37 LogMAR, Figure 9 diamonds) and eight out of

10 patients improved in stereopsis with six patients going

from no measurable stereopsis on the RanDot test to stere-

opsis in the range of 200–40 s of arc. These effects were

striking as at no point during the study was the fellow

eye patched. The transfer of the training effect from the

(a) (b)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Pre

trea

tmet

acu

ity (l

ogM

AR

)

Post treatment acuity (logMAR)

Aniso iPodAniso iPadAniso GogglesStrab iPodStrab GogglesStrab StereoscopeMixed iPodMixed GogglesMixed StereoscopeMean

1

1.5

2

2.5

3

3.5

4

1 1.5 2 2.5 3 3.5 4

Pre

trea

tmet

ste

rops

is(lo

g th

resh

old)

Post treatment stereopsis(log threshold)

Figure 9. Improvements in amblyopic eye visual acuity (a) and stereopsis (b) for the 73 published cases of amblyopia treated using the dichoptic con-

trast balanced approach (either global motion or Tetris). Data points above the unity lines indicate improvements. Participants treated with the stereo-

scope viewed dichoptic global motion stimuli. All other participants played the modified Tetris game. Data are shown as log threshold for stereopsis

and nil stereopsis results have been arbitrarily assigned a value of four for illustrative purposes. Twenty patients had no measurable stereopsis both

before and after treatment (data points overlap in to top right hand corner of panel b). Only visual acuity results were reported for the single case trea-

ted with an iPad device. Data are from ref. 35,36,59,77,89–91,93.



156


dichoptic global motion task to improved monocular and

binocular visual function in these adult patients suggested

that suppression of the amblyopic eye may play a causal

role in amblyopia and that reducing suppression enabled

plasticity with the visual cortex.

In order to translate these results into a clinical context

we incorporated the dichoptic contrast offset technique

into a version of the videogame Tetris (http://www.tetris.

com) which requires players to tessellate falling blocks

together. Some blocks are shown to the amblyopic eye at

high contrast and others to the fellow eye at a low contrast

tailored to each patient’s level of suppression. Both eyes

must be used simultaneously to play the game and success-

ful game play results in a reduction of the contrast differ-

ence between the two eyes. This game has been deployed

on a pair of video goggles with a separate screen for each

eye and portable iPod Touch and iPad devices for which

dichoptic viewing is enabled using either a lenticular over-

lay screen or red/green anaglyph glasses. To date there are

63 published cases of patients treated using the Tetris

method with ages ranging from 5 to 51 years and treatment

duration ranging from 5 to 40 h.89–94 Across studies the

average improvement in amblyopic eye visual acuity was

0.21 LogMAR (95% CI 0.17–0.25 LogMAR) and 42/63

patients (67%) of patients improved in stereopsis with 15/

63 patients (24%) recovering stereo after treatment having

no measurable stereo pre-treatment. Acuity and stereopsis

improvements for all published cases treated with either

the dot stimulus or the Tetris videogame are shown in

Figure 9. A univariate ANOVA conducted on the change in

LogMAR amblyopic eye acuity from pre to post treatment

with factors of amblyopia type (anisometropic vs strabismic

vs mixed), age and treatment duration in hours revealed no

significant main effects or interactions. In addition, the

proportion of patients who improved in stereopsis was

similar across the amblyopia subtypes of anisometropic

(10/32 improved, 31%), strabismic (7/19, 37%) and mixed

(4/11, 36%). Therefore these initial data suggest that the

effect of the treatment is independent of age and amblyopia

subtype. Randomized clinical trials are currently underway

2.5

3

3.5

4

Baseline Posttraining

Crossover

Ster

eops

is (l

og th

resh

old)

0.2

0.3

0.4

0.5

0.6

Baseline Posttraining

Crossover

Visu

al a

cuity

(log

MAR

)

1

1.5

2

2.5

3

3.5

4

Baseline Post sham Post anodaltDCS

Ste

reop

sis

(log

thre

shol

d)

(a)

(c)

(b)

Figure 10. A direct comparison between 2 weeks of monocular Tetris play (red lines) and dichoptic Tetris treatment (green lines) in 18 adult amblyo-

pes (n = 9 adults per group, panels a and b). Dichoptic treatment resulted in far greater improvements in acuity (panel a) and stereopsis (panel b) than

monocular treatment. Furthermore, participants in the monocular group exhibited substantial improvements when they were crossed over to binocu-

lar treatment (right most green lines). Panel (c) shows stereopsis at baseline and after sham or real anodal tDCS combined with binocular Tetris treat-

ment (n = 16 adults, randomized crossover design). The combined anodal tDCS and binocular Tetris treatment resulted in significantly greater

improvements in stereopsis than combined sham tDCS and binocular treatment. Error bars show S.E.M., nil stereopsis results were allocated a log

threshold of four for plotting. This substitution was not required for statistical significance. Data replotted from ref. 59,77.



157


to assess the efficacy of this treatment approach in larger

groups of patients.

Evidence to support the argument that the therapeutic

effect of the dichoptic treatment is due to strengthening of

binocular combination has recently been reported.59 In this

study, dichoptic treatment using the modified Tetris game

was directly compared to monocular treatment whereby all

the Tetris blocks were presented to the amblyopic eye at

high contrast and the fellow eye was patched. The results

were clear; dichoptic treatment was far superior to monoc-

ular treatment (Figure 10a,b) demonstrating that contrast

balanced binocular stimulation underlies the treatment

effect. Converging evidence has come from another recent

study demonstrating that dichoptic Tetris combined with

anodal tDCS of primary visual cortex results in greater

improvements in stereopsis than dichoptic Tetris alone77

(Figure 10c). In other words; the combination of two inter-

ventions that reduce suppression within the visual cortex

enhanced improvements in binocular visual function in

adult amblyopes.

Interim summary

Non-invasive brain stimulation techniques and dichoptic

perceptual learning have been found to induce improve-

ments in adults with amblyopia. These initial data indicate

that suppressive interactions within the visual cortex are a

viable target for amblyopia treatment and that suppression

gates plasticity within the amblyopic visual cortex of adults.

In particular, our novel dichoptic perceptual learning para-

digm, in the form of a videogame, has the potential to revo-

lutionize the treatment of amblyopia and provide a

treatment option for adults not currently treated.

Conclusions

A number of conclusions may be drawn from the evidence

presented in the preceding sections. Firstly, visual function

in the amblyopic eye is limited by the weak and noisy nature

of inputs from this eye to the visual cortex as well as sup-

pression of these inputs by information from the fellow eye,

although there is still much to learn about the connection

between these two phenomena. Crucially, when these

impediments to visual function are accounted for, intact

binocular mechanisms are revealed. Secondly, the strength

of binocular combination (or the reciprocal; the strength of

amblyopic eye suppression) can by objectively quantified

using psychophysical tasks that target the primary visual

cortex as well as dorsal or ventral extrastriate areas. The

measurements reveal that stronger suppression is associated

with poorer visual function in amblyopes and that suppres-

sion can be modulated in both amblyopes and observers

with normal vision using partial occlusion techniques and,

unexpectedly, short term occlusion of the weaker eye.

Thirdly, dichoptic perceptual learning, designed to

strengthen binocular combination by reducing suppression,

improves both stereopsis and acuity in adults and children

with amblyopia. These effects can be enhanced by non-inva-

sive brain stimulation techniques which can also improve

contrast sensitivity in their own right, possibly by reducing

suppression of inputs from the amblyopic to the cortex. All

of these conclusions are further strengthened by the recent

findings of the critical role played by binocular stimulations

in visual restoration in kittens that have been visually

deprived early in life (see the invited review by Prof. D E

Mitchell in this feature issue of Ophthalmic & Physiological

Optics). As a whole, these results lead us to question the

prevalent view that amblyopia is primarily a disorder of

monocular vision and should be treated accordingly with

monocular occlusion. If we are open to the possibility that

binocular interactions lie at the heart of amblyopia, then we

could be at the threshold of a new age of therapeutic inter-

ventions that don’t involve patching the fellow fixing eye.

Acknowledgements

BT is supported by grants from the Health Research Coun-

cil of New Zealand, The Marsden Fund and the University

of Auckland. RFH is supported by CIHR grants (#53346,

108-18 & 93073).

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Robert F. Hess is currently the Director of Research at the

Department of Ophthalmology, McGill University, Can-

ada, and Director of its Vision Research Unit which he

established in 1990. Previously, he was a Wellcome Senior

Lecturer at the University of Cambridge, Department of

Physiology (1982–1990), and a Meres Senior Fellow for

Medical Research at St. John’s College, Cambridge, (1977–1982). Robert obtained a DSc from the Aston University in

1998, a PhD in visual perception from the University of

Melbourne, in 1977, an MSc in neuropsychology from

Aston University, in 1972 and a Associate Diploma in

Optometry from the Queensland Institute of Technology,

in 1971. His research interests are broad and include nor-

mal and abnormal visual processing.

Benjamin Thompson completed his BSc and DPhil in

Experimental Psychology at the University of Sussex, UK.

He then completed postdoctoral fellowships within the

Department of Psychology, UCLA and the Department of

Ophthalmology, McGill University, Canada. Ben is cur-

rently an Associate Professor within the Department of

Optometry and Vision Science at the University of Auck-

land.



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Daniel H. Baker studied Psychology at the University of

Nottingham from 2000 to 2003. He then worked in indus-

try for a year before beginning a PhD at Aston University

under the supervision of Tim Meese. Daniel held postdoc-

toral positions at the University of Southampton (2007–2009), and Aston University (2009–2012). He took up a

lectureship at the University of York in January 2013. His

main research interests are spatial vision, binocular vision,

and motion perception, which he investigates using a com-

bination of psychophysics, EEG, and computational mod-

elling.



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